RESUMO
OBJECTIVE: Current treatment options for Allergic Rhinitis (AR) may have their own limitations and side effects. This study aimed to investigate the effects of Ma-al-Shaeer (MS), a novel natural formulation based on Hordeum vulgare, in the treatment of AR compared with Fexofenadine (FX). METHODS: A total of 77 patients with AR were divided into two groups: MS group (n=38) and FX group (n=39). The first group received 15 g of dried MS powder, and the second group received 60 mg of FX twice daily for 14 days. At baseline (week zero) and after the 14-day treatment period (week two), both groups were evaluated for sneezing, rhinorrhea, nasal congestion, nasal itching, post nasal drip, eye, throat, or ear symptoms, headache, cough, mental function, quality of life scores, blood eosinophil count and total IgE levels. Rhinitis control assessment tests were conducted at week zero and again at one week after cessation of treatment (week three) in both groups. RESULTS: All symptoms of AR except cough were significantly reduced in both groups; for nasal congestion, post nasal drip, and headache, the MS treatment was found to be superior. Rhinitis control was significantly increased after treatment in both groups (p value < 0.001). Both drugs significantly reduced total IgE levels. There was no significant change in eosinophil count in either group. CONCLUSION: MS formulation based on H. vulgare may be an effective treatment for AR. Further studies are needed to confirm the effect of MS as an alternative treatment in AR.
Assuntos
Antialérgicos/uso terapêutico , Antagonistas não Sedativos dos Receptores H1 da Histamina/uso terapêutico , Hordeum , Extratos Vegetais/uso terapêutico , Rinite Alérgica/tratamento farmacológico , Terfenadina/análogos & derivados , Adolescente , Adulto , Idoso , Antialérgicos/efeitos adversos , Antialérgicos/isolamento & purificação , Biomarcadores/sangue , Criança , Feminino , Antagonistas não Sedativos dos Receptores H1 da Histamina/efeitos adversos , Hordeum/química , Humanos , Imunoglobulina E/sangue , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/efeitos adversos , Extratos Vegetais/isolamento & purificação , Rinite Alérgica/diagnóstico , Rinite Alérgica/imunologia , Sementes , Terfenadina/efeitos adversos , Terfenadina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: In Japan, oral antihistamines are frequently used as the initial treatment for seasonal allergic rhinitis (SAR), and intranasal steroids are added when nasal symptoms worsen. This study aimed to evaluate whether starting treatment with fluticasone propionate nasal spray (FP) from the beginning of pollinosis symptoms and adding fexofenadine hydrochloride tablet (FEX) when SAR is aggravated could achieve improved amelioration of nasal symptoms throughout the pollen season in comparison with a treatment that involves starting with FEX and later adding FP. METHODS: In this pragmatic, randomized, open-label, parallel-group trial, 51 Japanese cedar pollinosis patients (age, 16-85 years) were randomly divided and administered FP 100 mcg twice daily as an initial drug with FEX 60 mg twice daily as an additional drug and the same treatment in the reverse order. Nasal symptoms were evaluated in a daily dairy using a 4-point scale. The primary outcome was area under curve of the line representing the daily total nasal symptom score in the pollen season on a graph. RESULTS: Initial treatment with FP was significantly (P = 0.0015) more effective than initial treatment with FEX in improving the primary outcome. The average daily total nasal symptom score in the initial treatment with FP group was better than that in the initial treatment with FEX group throughout the pollen season. CONCLUSIONS: Initiating treatment with FP and adding FEX might lead to improved outcomes for nasal symptoms in comparison with the same drugs administered in the reverse order.
Assuntos
Androstadienos/administração & dosagem , Antialérgicos/administração & dosagem , Rinite Alérgica Sazonal/tratamento farmacológico , Terfenadina/análogos & derivados , Adulto , Androstadienos/efeitos adversos , Androstadienos/uso terapêutico , Antialérgicos/efeitos adversos , Antialérgicos/uso terapêutico , Feminino , Fluticasona , Humanos , Masculino , Pessoa de Meia-Idade , Sprays Nasais , Pólen , Comprimidos , Terfenadina/administração & dosagem , Terfenadina/efeitos adversos , Terfenadina/uso terapêutico , Resultado do TratamentoRESUMO
Yokukansan (YKS) has been used in Japan as a remedy for neurosis, insomnia, and children with night crying. In a previous study, we reported that YKS controls scratching behavior and inhibits the development of atopic dermatitis (AD)-like lesions in NC/Nga mice. In this study, we investigated the effects of YKS on the development of AD-like lesions in socially isolated NC/Nga mice compared with the effects of fexofenadine and elucidated the mechanism of the ameliorating effect of YKS on the skin lesions. Ten-week-old male NC/Nga mice were divided into three groups (n = 5/group): the conventional control, the YKS-treated, and the fexofenadine-treated groups, and were kept isolated under conventional conditions for 6 weeks. Measurements were made of dermatitis scores and transepidermal water loss (TEWL), scratching and grooming behaviors. Immunohistochemistry and mRNA levels were also evaluated. We performed similar experiments under specific pathogen free (SPF) conditions that served as a SPF control. YKS and fexofenadine inhibited the aggravation of skin lesions and decreased TEWL, but only YKS decreased the numbers of scratching and pathologic grooming behaviors. Immunohistochemistry and RT-PCR revealed that N-methyl-D: -aspartate (NMDA) receptor expression was increased in the skin of conventional control mice and was decreased in YKS-treated mice. Glutamate transporter-1 (GLT-1) mRNA levels were decreased in the skin of conventional control mice and were increased in YKS-treated mice. The results indicate that YKS ameliorates AD-like skin lesions in NC/Nga mice through a mechanism distinct from that of fexofenadine. Furthermore, the effects of YKS are suggested to be mediated via glutamate signaling in the skin lesions.
Assuntos
Ansiolíticos/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicina Kampo , Pele/efeitos dos fármacos , Animais , Ansiolíticos/efeitos adversos , Dermatite Atópica/fisiopatologia , Medicamentos de Ervas Chinesas/efeitos adversos , Transportador 2 de Aminoácido Excitatório/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/efeitos adversos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos , Pele/patologia , Isolamento Social , Terfenadina/administração & dosagem , Terfenadina/efeitos adversos , Terfenadina/análogos & derivadosRESUMO
BACKGROUND: Second-generation oral H1-antihistamines have become a mainstay of treatment for the symptoms of seasonal allergic rhinitis; however, the effect of olopatadine has not been widely reported to date. OBJECTIVES: To evaluate the efficacy of 2 oral H1-antihistamines, olopatadine and fexofenadine, in the treatment of the nasal symptoms of Japanese cedar pollinosis and their possible side effects. METHODS: This was a randomized, double-blind, placebo-controlled, crossover study conducted in an environmental exposure unit (EEU). Twenty volunteers suffering from Japanese cedar pollinosis were randomly divided into 3 groups and exposed to cedar pollen in the EEU with oral administration of olopatadine hydrochloride (5 mg), fexofenadine hydrochloride (60 mg), or placebo 1 hour prior to pollen exposure. Nasal symptoms, activity impairment, and subjective sleepiness were self-assessed during the study period. Attention was measured using the digit cancellation test. The trial was repeated after 4 and 7 weeks. RESULTS: Compared with placebo, olopatadine significantly improved nasal symptoms and activity impairment during pollen exposure (P < .05). There was no significant relief of nasal discharge or nasal congestion with fexofenadine throughout the 5-hour exposure to cedar pollen. Furthermore, olopatadine significantly reduced nasal congestion during the first 2 hours, as well as sneezing and nasal discharge 4 hours after admission to the EEU compared with fexofenadine (P < .05). There was no significant difference in the effect on subjective sleepiness among the 3 groups, and all 3 agents had little effect on attention. CONCLUSIONS: These findings suggest that olopatadine is more effective than placebo and fexofenadine in improving nasal symptoms of Japanese cedar pollinosis.
Assuntos
Alérgenos/imunologia , Dibenzoxepinas , Antagonistas não Sedativos dos Receptores H1 da Histamina , Pólen/imunologia , Rinite Alérgica Sazonal/tratamento farmacológico , Adulto , Cryptomeria/imunologia , Dibenzoxepinas/administração & dosagem , Dibenzoxepinas/efeitos adversos , Método Duplo-Cego , Feminino , Seguimentos , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Atividade Motora/imunologia , Cloridrato de Olopatadina , Rinite Alérgica Sazonal/imunologia , Sono/efeitos dos fármacos , Espirro/efeitos dos fármacos , Terfenadina/administração & dosagem , Terfenadina/efeitos adversos , Terfenadina/análogos & derivados , Resultado do TratamentoRESUMO
INTRODUCTION: Drug-induced QT interval prolongation is a major concern in new drug candidate development. This study presents a method of assessment of drug-induced QT interval prolongation without need for QT correction in conscious Beagle dogs and Cynomolgus monkeys monitored by telemetry. Accuracy and reliability are analysed by comparison with a reference QT correction method (Holzgrefe) from experiments performed with reference substances terfenadine, thioridazine and sotalol. METHODS: The QT shift method principle is assessment of any drug-induced QT interval shift directly from the individual QT/RR relationship. The individual QT/RR relationship is built from a treatment-free 24-hour recording period. QT and RR intervals are determined from a beat-to-beat analysis. A probabilistic method is used to define the individual QT/RR relationships. Checks were performed to compare results obtained with the QT shift method and the QT correction methods. The robustness of the QT shift method was tested under various conditions of drug-induced heart rate change (i.e. normal, bradycardia and tachycardia). RESULTS: The extent of agreement with the used reference QT correction method, Holzgrefe formula, was excellent (3-4 ms) in both animal species under the various drug induced effects on heart rate. The statistical sensitivity threshold for detection of QT prolongation according to a standard safety pharmacology study design was 7-8 ms. DISCUSSION: When combined with the probabilistic determination of individual QT/RR relationships, this simple method provides a direct assessment of a drug-induced effect on QT interval, without any curve fitting or application of correction formula. Despite noticeably different shapes in QT/RR relationships, the QT shift method is applicable to both Beagle dogs and Cynomolgus monkeys. It is likely that the QT shift method will be particularly helpful in problematic cases, enabling detection of drug-induced prolongation of less than 10 ms.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Eletrocardiografia/instrumentação , Eletrocardiografia/normas , Frequência Cardíaca/fisiologia , Síndrome do QT Longo/induzido quimicamente , Animais , Antiarrítmicos/efeitos adversos , Antiarrítmicos/farmacologia , Cães , Antagonistas de Dopamina/efeitos adversos , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Antagonistas não Sedativos dos Receptores H1 da Histamina/efeitos adversos , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Macaca fascicularis , Masculino , Modelos Estatísticos , Fenetilaminas/efeitos adversos , Fenetilaminas/farmacologia , Padrões de Referência , Sensibilidade e Especificidade , Sotalol/efeitos adversos , Sotalol/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Telemetria , Terfenadina/efeitos adversos , Terfenadina/farmacologia , Tioridazina/efeitos adversos , Tioridazina/farmacologiaRESUMO
The oral administration of fexofenadine 120 mg daily is a common treatment of seasonal allergic rhinitis (SAR). It reduces the H1 receptor-mediated symptoms, such as sneezing, pruritus, and nasal secretion as well as non-nasal symptoms such as conjunctivitis. The objective was to assess the effect of fexofenadine on nasal symptoms (such as nasal obstruction) in seasonal allergic rhinitis. A placebo-controlled, double-blind, randomized, cross-over study was performed which yielded evidence that two-week therapy with fexofenadine 120 mg daily in patients with SAR also relieves nasal obstruction and congestion. The parameters of nasal obstruction were evaluated by means of rhinoscopy, a subjective symptom score, and active anterior rhinomanometry. The subjective evaluation of nasal obstruction/congestion as recorded by the patient every 15 minutes for 4.5 hours after nasal allergen provocation showed a significant difference of the AUC (p = 0.025) between fexofenadine and placebo with a 12.8% lower obstruction after fexofenadine. The swelling of the nasal mucosa, which was assessed by rhinoscopy for 4.5 hours after nasal allergen provocation, was 21% lower after treatment with fexofenadine (p = 0.041). In this double-blind, placebo-controlled trial, subjective patient ratings as well as objective investigator assessments demonstrate the anti-obstructive effect of fexofenadine in nasal allergen challenge.
Assuntos
Antígenos de Plantas/imunologia , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Pólen/imunologia , Rinite Alérgica Sazonal/tratamento farmacológico , Terfenadina/análogos & derivados , Administração Oral , Método Duplo-Cego , Antagonistas não Sedativos dos Receptores H1 da Histamina/efeitos adversos , Humanos , Obstrução Nasal , Testes de Provocação Nasal , Ventilação Pulmonar/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/fisiopatologia , Rinomanometria , Terfenadina/administração & dosagem , Terfenadina/efeitos adversosRESUMO
OBJECTIVE: Allergic rhinitis, a disease that impairs quality of life, is characterized by inflammation due to an allergic reaction. Fexofenadine is a second-generation histamine receptor blocker well known for its potent interaction with this inflammatory process. The main aim of this study was to further clarify the anti-inflammatory effects exerted by fexofenadine in patients with intermittent allergic rhinitis. METHODS: Twenty patients with intermittent allergic rhinitis due to birch and mugwort pollen were enrolled. Fexofenadine was administered once a day at a dose of 120 mg. Clinical improvement was assessed by a symptom score, and nasal airway flows were measured by anterior rhinomanometry at baseline and after 2 weeks of treatment with fexofenadine. Nasal smears were tested for eosinophils and nasal lavage fluid were examined for histamine, cysteinyl leukotrienes, soluble intercellular adhesion molecule-1, eosinophil cationic protein, and albumin by enzyme-linked immunosorbent assay. All the tests were performed during the pollen season. RESULTS: Fexofenadine induced a significant improvement in nasal and ocular symptoms (P < .001), nasal edema and secretion (P < .001), and nasal airway flow (P < .001). The clinical improvement was related to a significant reduction in all inflammatory mediators (P < .01 in all cases). CONCLUSION: This study demonstrates that fexofenadine is able to mediate significant changes in different nasal lavage markers from patients with intermittent allergic rhinitis. The changes observed in the markers analyzed in both nasal secretions and serum are attributable to the anti-inflammatory effects of fexofenadine in vivo.
Assuntos
Anti-Inflamatórios/administração & dosagem , Mediadores da Inflamação/imunologia , Líquido da Lavagem Nasal/imunologia , Rinite Alérgica Sazonal/tratamento farmacológico , Terfenadina/análogos & derivados , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Antígenos de Plantas/efeitos adversos , Antígenos de Plantas/imunologia , Artemisia/imunologia , Betula/imunologia , Progressão da Doença , Proteína Catiônica de Eosinófilo/análise , Feminino , Histamina/análise , Humanos , Mediadores da Inflamação/análise , Molécula 1 de Adesão Intercelular/análise , Leucotrieno D4/análise , Masculino , Pessoa de Meia-Idade , Líquido da Lavagem Nasal/química , Pólen/efeitos adversos , Pólen/imunologia , Rinite Alérgica Sazonal/imunologia , Terfenadina/administração & dosagem , Terfenadina/efeitos adversos , Resultado do TratamentoRESUMO
In safety pharmacology, a number of preclinical models for detecting drug-induced proarrhythmia liability have been recently introduced that utilize hard endpoints: early after depolarziations (EADs), torsades de pointes (TdP) or both as the principal biomarker. To explore the validity of four of the most common of these models, (the isolated canine/rabbit left ventricular wedge preparation, the isolated rabbit heart, the methoxamine-pretreated anaesthetized rabbit and the complete, chronic AV-blocked (CAVB) dog (conscious and anaesthetized), the present article reviews published data sets for three drugs with recognized and different human TdP liabilities (cisparide, terfenadine and moxifloxacinin). Finally, this review considers the value of inclusion of analysis of beat-to-beat variability of repolarization (BVR) in TdP liability testing to improve sensitivity and specificity.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Eletrocardiografia/métodos , Torsades de Pointes/induzido quimicamente , Animais , Compostos Aza/efeitos adversos , Cisaprida/efeitos adversos , Cães , Avaliação Pré-Clínica de Medicamentos , Fluoroquinolonas , Humanos , Modelos Biológicos , Moxifloxacina , Quinolinas/efeitos adversos , Coelhos , Medição de Risco/métodos , Terfenadina/efeitos adversosRESUMO
OBJECTIVES: We examined how repolarization and depolarization abnormalities contribute to the development of extrasystoles and subsequent ventricular fibrillation (VF) in a model of the Brugada syndrome. BACKGROUND: Repolarization and depolarization abnormalities have been considered to be mechanisms of the coved-type ST-segment elevation (Brugada-electrocardiogram [ECG]) and development of VF in the Brugada syndrome. METHODS: We used high-resolution (256 x 256) optical mapping techniques to study arterially perfused canine right ventricular wedges (n = 20) in baseline and in the Brugada-ECG produced by administration of terfenadine (5 micromol/l), pinacidil (2 micromol/l), and pilsicainide (5 micromol/l). We recorded spontaneous episodes of phase 2 re-entrant (P2R)-extrasystoles and subsequent self-terminating polymorphic ventricular tachycardia (PVT) or VF under the Brugada-ECG condition and analyzed the epicardial conduction velocity and action potential duration (APD) restitutions in each condition. RESULTS: Forty-one episodes of spontaneous P2R-extrasystoles in the Brugada-ECG were successfully mapped in 9 of 10 preparations, and 33 of them were originated from the maximum gradient of repolarization (GR(max): 176 +/- 54 ms/mm) area in the epicardium, leading to PVT (n = 12) or VF (n = 5). The epicardial GR(max) was not different between PVT and VF. Wave-break during the first P2R-extrasystole produced multiple wavelets in all VF cases, whereas no wave-break or wave-break followed by wave collision and termination occurred in PVT cases. Moreover, conduction velocity restitution was shifted lower and APD restitution was more variable in VF cases than in PVT cases. CONCLUSIONS: Steep repolarization gradient in the epicardium but not endocardium develops P2R-extrasystoles in the Brugada-ECG condition, which might degenerate into VF by further depolarization and repolarization abnormalities.
Assuntos
Fármacos Cardiovasculares/efeitos adversos , Técnicas Eletrofisiológicas Cardíacas/métodos , Sistema de Condução Cardíaco/efeitos dos fármacos , Fibrilação Ventricular/fisiopatologia , Potenciais de Ação , Animais , Modelos Animais de Doenças , Cães , Eletrocardiografia , Endocárdio , Cardiopatias/induzido quimicamente , Ventrículos do Coração/efeitos dos fármacos , Lidocaína/efeitos adversos , Lidocaína/análogos & derivados , Masculino , Pericárdio , Pinacidil/efeitos adversos , Taquicardia Ventricular/induzido quimicamente , Taquicardia Ventricular/fisiopatologia , Terfenadina/efeitos adversos , Fibrilação Ventricular/induzido quimicamenteRESUMO
In a previous study, cetirizine and fexofenadine similarly relieved seasonal allergic rhinitis symptoms in the first 5 hours, but cetirizine was more effective at 21-24 hours postdose. This randomized, double-blind, placebo-controlled study compared the response to treatment between 5 and 12 hours. Eligible ragweed allergic subjects were exposed to pollen in the Environmental Exposure Unit and randomized (n = 599) to a single dose of cetirizine, 10 mg; fexofenadine, 180 mg; or placebo (2.5:2.5:1). The primary efficacy end point was the change from baseline in total symptom severity complex (TSSC) score at 12 hours postdose. TSSC score was the sum of self-rated scores (0 = absent to 3 = severe) for runny nose, sneezing, itchy nose/palate/throat, and itchy/watery eyes, recorded half-hourly. Mean baseline TSSC scores were similar: 9.2, cetirizine and fexofenadine; 8.9, placebo. Reductions in TSSC scores from baseline were 4.3 at 12 hours and 5.0 overall (i.e., average over 5-12 hours postdose) for cetirizine and 3.4 and 4.4, respectively, for fexofenadine. Cetirizine produced a 26% greater reduction in TSSC at 12 hours (p = 0.001) and 14% greater reduction in TSSC overall (p = 0.006) compared with fexofenadine. Cetirizine and fexofenadine reduced TSSC scores (p < 0.001) and individual symptoms (p < 0.05) more than placebo. However, cetirizine was more effective than fexofenadine (p < 0.05) for runny nose and sneezing (12 hours and overall), itchy/watery eyes (12 hours), and itchy nose/throat/palate (overall). Incidence of treatment-emergent adverse events and somnolence were similar among groups: cetirizine, 25.3 and 0.8%, respectively; fexofenadine, 29.6 and 0%, respectively; placebo, 35.0 and 0%, respectively. In conclusion, cetirizine produced greater relief of seasonal allergic rhinitis symptoms than fexofenadine at 12 hours postdose and over the 5- to 12-hour postdose period.
Assuntos
Antialérgicos/uso terapêutico , Cetirizina/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Rinite Alérgica Sazonal/tratamento farmacológico , Terfenadina/análogos & derivados , Adolescente , Adulto , Idoso , Alérgenos , Antialérgicos/efeitos adversos , Cetirizina/efeitos adversos , Método Duplo-Cego , Feminino , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pólen , Rinite Alérgica Sazonal/diagnóstico , Terfenadina/efeitos adversos , Terfenadina/uso terapêuticoRESUMO
The utility of halothane-anaesthetized guinea-pigs as an in vivo model for predicting the clinical potential of a drug to induce QT interval prolongation was assessed using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of D-sotalol (0.3 mg kg(-1)) and terfenadine (0.3 mg kg(-1)), blockers of a rapid component of delayed rectifier potassium currents, prolonged the QT interval by 32+/-7 and 23+/-6 ms, respectively, whereas chromanol 293B (1 mg kg(-1)), a blocker of a slow component of delayed rectifier potassium currents, lengthened it by 33+/-8 ms. The extent of the QT interval prolongation by these drugs was greater than those in previous reports using pentobarbital-anaesthetized guinea-pigs. The MAP duration at the control was shortened by decreasing the pacing cycle length from 400 to 200 ms, but the MAP duration at each cycle length was prolonged by D-sotalol. The formulas of Van de Water, Matsunaga, Fridericia and Bazett showed good correlation of the repolarization period when compared with the MAP duration at a pacing cycle length of 400 ms. The halothane-anaesthetized guinea-pig model may possess enough sensitivity to detect drug-induced QT interval prolongation, indicating that halothane anaesthesia can reduce the repolarization reserve of the heart in vivo.
Assuntos
Anestésicos Inalatórios/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Halotano/farmacologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Coração/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Potenciais de Ação/efeitos dos fármacos , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/efeitos adversos , Algoritmos , Anestésicos Inalatórios/administração & dosagem , Animais , Cromanos/administração & dosagem , Cromanos/farmacologia , Canais de Potássio de Retificação Tardia/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Eletrocardiografia/efeitos dos fármacos , Cobaias , Halotano/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Modelos Lineares , Masculino , Modelos Animais , Preparações Farmacêuticas/administração & dosagem , Bloqueadores dos Canais de Potássio/administração & dosagem , Bloqueadores dos Canais de Potássio/farmacologia , Reprodutibilidade dos Testes , Sotalol/administração & dosagem , Sotalol/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Terfenadina/administração & dosagem , Terfenadina/efeitos adversos , Fatores de TempoRESUMO
INTRODUCTION: The HERG channel is widely used for the assessment of proarrhythmic risk for new drugs. HERG channel blockers obstruct channel functions through various mechanisms, which usually show time dependence, voltage dependence, and state dependence. The voltage protocol and temperature may affect the estimation of drug potency, but limited information is available in this regard. The purpose of this study was to evaluate the influence of voltage protocol and temperature on predicting the potency of HERG channel blockers, and to determine electrophysiological approaches for new drugs screening studies. METHOD: Whole-cell patch-clamp electrophysiology was carried out by utilizing different voltage step protocols to examine the potency of compounds known to preferentially block the channel in the closed (ketoconazole and BeKm-1), open, and/or inactivated states (E-4031, astemizole, and terfenadine) in HEK293 cells transfected with HERG cDNA at room temperature and near-physiological temperature. RESULTS: Drug potency determined using different voltage protocols varied dependent on the mechanisms of drug actions. For most compounds, the IC(50) values obtained with a long pulse step protocol at room temperature were close to those determined with the voltage protocols designed to disclose their intrinsic potency. Relative to room temperature, the potency of E-4031, terfenadine, and ketoconazole was not changed at approximately 35 degrees C, but potency of astemizole was reduced. DISCUSSION: The long pulse step protocol with room temperature can be selected for HERG channel safety screening studies. Alternative voltage protocols or temperatures should be considered if HERG study results are not consistent with other cardiac safety assessments.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Técnicas de Patch-Clamp/métodos , Bloqueadores dos Canais de Potássio/efeitos adversos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Astemizol/efeitos adversos , Linhagem Celular , Relação Dose-Resposta a Droga , Temperatura Alta , Humanos , Concentração Inibidora 50 , Cetoconazol/efeitos adversos , Preparações Farmacêuticas/classificação , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Venenos de Escorpião/efeitos adversos , Terfenadina/efeitos adversos , TransfecçãoRESUMO
Although antihistamine-decongestant combinations are frequently used for allergic rhinitis, published data about the onset of action of these combination agents are limited. This randomized, double-blind, placebo-controlled, parallel-group study investigated the onset of action, efficacy, and safety of fexofenadine HCl 60 mg/pseudoephedrine HCl 120 mg or placebo in patients with moderate-to-severe seasonal allergic rhinitis in an allergen exposure unit. Assessments included major symptom complex (MSC) score (sum of sneezing, itchy nose, runny nose, watery eyes, itchy eyes, itchy ears/throat, and stuffy nose), and total symptom complex (TSC) score (MSC symptoms plus nose blows, sniffles, postnasal drip, and cough). Onset of action was defined as the first time that two consecutive, statistically significant absolute changes in MSC scores from baseline were achieved for study drug relative to placebo. The onset of action for the combination was 60 minutes (mean absolute MSC change from baseline: -6.9 +/- 0.3 for the combination compared with -5.9 +/- 0.3 for placebo from a baseline of 17.0 and 16.8, respectively; p < 0.05) for the modified intention-to-treat population (n = 486). Reductions in absolute MSC scores were significantly greater with the combination than placebo at all subsequent time points (p < 0.01). The combination resulted in significantly greater reductions compared with placebo for percent MSC, absolute TSC, and percent TSC scores at 60 minutes postdose (all p < 0.05) and throughout the study (all p < 0.05). The incidence of adverse events was 1.6 and 3.3% for the combination and placebo, respectively. In conclusion, fexofenadine HCl 60 mg/pseudoephedrine HCl 120 mg is effective in the treatment of patients with moderate-to-severe seasonal AR, with an onset of action of 60 minutes and a good safety profile.
Assuntos
Broncodilatadores/farmacologia , Efedrina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Rinite Alérgica Sazonal/tratamento farmacológico , Terfenadina/análogos & derivados , Terfenadina/farmacologia , Adolescente , Adulto , Alérgenos/imunologia , Ambrosia/imunologia , Testes de Provocação Brônquica , Broncodilatadores/efeitos adversos , Broncodilatadores/uso terapêutico , Criança , Método Duplo-Cego , Combinação de Medicamentos , Efedrina/efeitos adversos , Efedrina/uso terapêutico , Feminino , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pólen/imunologia , Rinite Alérgica Sazonal/etiologia , Terfenadina/efeitos adversos , Terfenadina/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
Early recognition of potential QT/TdP liability is now an essential component of the drug discovery/drug development program. The hERG assay is an indispensable step and a high-quality assay must accompany any investigational new drug (IND) application. While it is the gold standard at present, the hERG assay is too labor-intensive and too low throughput to be used as a screen early in the discovery/development process. A variety of indirect high throughput screens have been used.
Assuntos
Morte Súbita Cardíaca/etiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/metabolismo , Avaliação Pré-Clínica de Medicamentos/normas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Humanos , Síndrome do QT Longo/etiologia , Terfenadina/efeitos adversos , Terfenadina/farmacologiaRESUMO
There is published evidence that cetirizine has a longer duration of effect than fexofenadine. This study compared duration of effect and other measures of efficacy of cetirizine, 10 mg; fexofenadine, 180 mg; and placebo in allergic subjects exposed to pollen in the Environmental Exposure Unit. Eligible subjects (n = 575) were exposed to ragweed pollen (day 1, 7 hours; day 2, 5 hours) and randomized in double-blind fashion to once-daily cetirizine, 10 mg; fexofenadine, 180 mg; or placebo. The total symptom severity complex (TSSC) score, the primary efficacy variable, was based on four rhinoconjunctivitis symptoms rated at 20-minute intervals. Treatment evaluation was divided into three periods: period 1 TSSC, average of 15 scores obtained 0-5 hours after the first dose; period 2 TSSC, average of 9 scores obtained 21-24 hours after the first dose; and period 3 TSSC, average of 6 scores obtained 0-2 hours after the second dose. The primary efficacy end point was the change from baseline TSSC at period 2. Baseline TSSC was the final pretreatment score on day 1 and was 9.7 for cetirizine, 9.8 for fexofenadine, and 9.7 for placebo. For the primary efficacy end point, the reduction in baseline TSSC at period 2 was greater for cetirizine (-3.6) compared with fexofenadine (-2.7; p < 0.001) and placebo (-2.0; p < 0.001), representing a 33% greater reduction for cetirizine versus fexofenadine. Cetirizine continued to reduce TSSC more than fexofenadine (-5.2 versus -4.6; p = 0.017) and placebo (-3.9; p < 0.001) (period 3). Similar efficacy was observed in period 1 for both active treatments. Treatment-related adverse events were similar in all groups with an incidence of somnolence of 1.3% for both active medications. In conclusion, cetirizine produced a 33% greater reduction in SAR symptoms over the 21- to 24-hour interval after the first dose and for 40 minutes after the second dose, indicating a superior and longer duration of effect, which is relevant because both are once-daily medications. Onset of action was comparable and both treatments were safe and well tolerated.
Assuntos
Alérgenos/efeitos adversos , Antialérgicos/uso terapêutico , Testes de Provocação Brônquica , Cetirizina/uso terapêutico , Exposição Ambiental/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Pólen/efeitos adversos , Terfenadina/análogos & derivados , Terfenadina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Poluentes Atmosféricos/efeitos adversos , Antialérgicos/efeitos adversos , Canadá/epidemiologia , Cetirizina/efeitos adversos , Conjuntivite Alérgica/tratamento farmacológico , Conjuntivite Alérgica/etiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Rinite Alérgica Sazonal/tratamento farmacológico , Rinite Alérgica Sazonal/etiologia , Índice de Gravidade de Doença , Terfenadina/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the therapeutic efficacy of fexofenadine hydrochloride (Allegra(R) tablets), an antihistaminic launched in 2001, in patients with cedar pollinosis by dividing them into two groups for comparison, i.e. the early-treatment group in which treatment was started before the initial day of the pollen scattering, and the therapeutic-treatment group in which treatment was started after the initial day of the pollen scattering. METHODS: Early-treatment group: patients who visited the hospital before the initial day of cedar pollen scattering were orally given one tablet of the drug twice daily. Therapeutic-treatment group: patients who visited the hospital after the initial day of cedar pollen scattering were orally given one tablet of the drug twice daily. The total number of cases in which the efficacy evaluation was possible was 37 cases (19 cases of the early-treatment group and 18 cases of the therapeutic-treatment group) after application of exclusion criteria. RESULTS: The useful rate of moderately effective or better against sneeze was 90% in the early-treatment group, and 78% in the therapeutic-treatment group, and there was a significant difference between both groups. The degree of satisfaction in the early-treatment group was 3.8 points, and 4.2 points in the therapeutic-treatment group, and the therapeutic-treatment group showed a higher score, but there was no significant difference between both groups. As adverse reaction, there was only one case of mild dizziness (2.7%), and no other adverse reactions such as sleepiness were observed. CONCLUSIONS: It was suggested that fexofenadine hydrochloride administered in patients with cedar pollinosis from before substantial pollen scattering might control their symptoms to mild ones, and might control worsening of their symptoms after the substantial pollen scattering, and, therefore, the drug was considered to be useful in early therapy.
Assuntos
Antialérgicos/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Pólen , Rinite Alérgica Sazonal/tratamento farmacológico , Terfenadina/análogos & derivados , Terfenadina/uso terapêutico , Adolescente , Adulto , Idoso , Antialérgicos/efeitos adversos , Cedrus , Esquema de Medicação , Feminino , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Pré-Medicação , Rinite Alérgica Sazonal/classificação , Rinite Alérgica Sazonal/etiologia , Terfenadina/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The combination of montelukast (ML) and loratadine (LT) has previously been shown to be superior to either drug alone in managing seasonal allergic rhinitis (SAR), whilst fexofenadine (FEX) has been shown to be better than LT as monotherapy. OBJECTIVES: We wished to compare ML + LT vs. FEX alone for effects on daily measurements (am/pm) of peak inspiratory flow (PIF) and symptoms. METHODS: Thirty-seven patients with SAR (skin prick positive to grass pollen) were randomised into a single-blind, double-dummy placebo (PL)-controlled cross-over study during the grass pollen season, comparing 2 weeks of once daily treatment with (a) 120mg FEX or (b) 10mg ML + 10mg LT. There was a 7-10 day placebo run-in and washout prior to each randomised treatment. The average of am/pm PIF (the primary outcome variable) was analysed. Patients recorded their symptom scores (from 0 to 3) twice daily, for nasal blockage, discharge, itching and sneezing with; total eye symptoms, ocular cromoglycate use, and daily activity. The total nasal symptom score was calculated as a composite (out of 24). RESULTS: There were no significant differences between baselines after the run-in and washout placebos for any variables. There were significant (P < 0.05, Bonferroni) improvements in all symptoms and PIF compared to pooled placebo with both treatments for all end-points, but no differences between the two treatment regimes (as means and within-treatment 95% confidence intervals): PIF: PL 102 (98-107), FEX 111 (107-116), ML+LT 113 (109-118); total nasal symptoms: PL 7.4 (6.7-2.0), FEX 5.0 (4.3-5.7), ML + LT 4.0 (3.3-4.7). CONCLUSIONS: Once daily FEX as monotherapy was equally effective as the combination of once daily ML + LT in improving nasal peak flow and controlling symptoms in SAR. Further studies are indicated to assess whether ML confers additional benefits to FEX in SAR.
Assuntos
Acetatos/administração & dosagem , Antialérgicos/administração & dosagem , Antagonistas de Leucotrienos/administração & dosagem , Loratadina/administração & dosagem , Cavidade Nasal/fisiopatologia , Ventilação Pulmonar/efeitos dos fármacos , Quinolinas/administração & dosagem , Rinite Alérgica Sazonal/tratamento farmacológico , Terfenadina/análogos & derivados , Terfenadina/administração & dosagem , Acetatos/efeitos adversos , Acetatos/uso terapêutico , Adulto , Antialérgicos/efeitos adversos , Antialérgicos/uso terapêutico , Estudos Cross-Over , Ciclopropanos , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Antagonistas de Leucotrienos/efeitos adversos , Antagonistas de Leucotrienos/uso terapêutico , Loratadina/efeitos adversos , Loratadina/uso terapêutico , Poaceae/imunologia , Pólen/imunologia , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Rinite Alérgica Sazonal/fisiopatologia , Método Simples-Cego , Testes Cutâneos , Sulfetos , Terfenadina/efeitos adversos , Terfenadina/uso terapêuticoRESUMO
Second generation antihistamines have been employed in the treatment of seasonal allergic rhinitis for many years. However, their effects on two distinctive Mediterranean allergic conditions, viz. Parietaria pollinosis and cypress pollinosis, have been scarcely investigated, so far. A comparative efficacy and side effect trial of astemizole and terfenadine in the treatment of seasonal allergic rhinitis due to either Parietaria or cypress pollen was carried out in 27 adult patients, according to a double-blind, double-dummy parallel-group design. Airborne pollen monitoring allowed comparison of symptom scores with pollen counts. Seven patients (26%) withdrew, due to poor symptom control. In contrast, in a subset of 15 patients who completed the trial, treatment led to a substantial and statistically significant decline in symptom severity in both the astemizole and the terfenadine study group. However, no statistically significant inter-group differences could be detected.